Machado-Joseph Disease Patients Research Articles

The vestibular symptomatology of Machado-Joseph Disease.

Machado Joseph Disease (MJD) is an autosomal dominant neurodegenerative disease. In previous studies, we described significant bilateral horizontal Vestibulo-Ocular Reflex (VOR) deficit within this population without any reference to the presence of vestibular symptomatology. To evaluate whether, beyond cerebellar ataxia complaints, MJD patients have typical vestibular symptomatology corresponding to the accepted diagnostic criteria of Bilateral Vestibulopathy (BVP) according to the definition of the International Barany Society of Neuro-Otology. Twenty-one MJD, 12 clinically stable chronic Unilateral Vestibulopathy (UVP), 15 clinically stable chronic BVP, and 22 healthy Controls underwent the video Head Impulse Test (vHIT) evaluating VOR gain and filled out the following questionnaires related to vestibular symptomatology: The Dizziness Handicap Inventory (DHI), the Activities-specific Balance Confidence Scale (ABC), the Vertigo Visual Scale (VVS) and the Beck Anxiety Inventory (BAI). The MJD group demonstrated significant bilateral vestibular impairment with horizontal gain less than 0.6 in 71% of patients (0.54±0.17). Similar to UVP and BVP, MJD patients reported a significantly higher level of symptoms than Controls in the DHI, ABC, VVS, and BAI questionnaires. MJD demonstrated significant VOR impairment and clinical symptoms typical of BVP. We suggest that in a future version of the International Classification of Vestibular Disorders (ICVD), MJD should be categorized under a separate section of central vestibulopathy with the heading of bilateral vestibulopathy. The present findings are of importance regarding the clinical diagnosis process and possible treatment based on vestibular rehabilitation.

Spermidine treatment: induction of autophagy but also apoptosis?

Machado-Joseph disease (MJD), also known as spinocerebellar ataxia type 3, is a fatal neurodegenerative disease that causes loss of balance and motor co-ordination, eventually leading to paralysis. It is caused by the autosomal dominant inheritance of a long CAG trinucleotide repeat sequence within the ATXN3 gene, encoding for an expanded polyglutamine (polyQ) repeat sequence within the ataxin-3 protein. Ataxin-3 containing an expanded polyQ repeat is known to be highly prone to intraneuronal aggregation, and previous studies have demonstrated that protein quality control pathways, such as autophagy, are impaired in MJD patients and animal models of the disease. In this study, we tested the therapeutic potential of spermidine on zebrafish and rodent models of MJD to determine its capacity to induce autophagy and improve functional output. Spermidine treatment of transgenic MJD zebrafish induced autophagy and resulted in increased distances swum by the MJD zebrafish. Interestingly, treatment of the CMVMJD135 mouse model of MJD with spermidine added to drinking water did not produce any improvement in motor behaviour assays, neurological testing or neuropathology. In fact, wild type mice treated with spermidine were found to have decreased rotarod performance when compared to control animals. Immunoblot analysis of protein lysates extracted from mouse cerebellar tissue found little differences between the groups, except for an increased level of phospho-ULK1 in spermidine treated animals, suggesting that autophagy was indeed induced. As we detected decreased motor performance in wild type mice following treatment with spermidine, we conducted follow up studies into the effects of spermidine treatment in zebrafish. Interestingly, we found that in addition to inducing autophagy, spermidine treatment also induced apoptosis, particularly in wild type zebrafish. These findings suggest that spermidine treatment may not be therapeutically beneficial for the treatment of MJD, and in fact warrants caution due to the potential negative side effects caused by induction of apoptosis.

Drug repurposing of dopaminergic drugs to inhibit ataxin-3 aggregation

The accumulation of mutant ataxin-3 (Atx3) in neuronal nuclear inclusions is a pathological hallmark of Machado-Joseph disease (MJD), also known as Spinocerebellar Ataxia Type 3. Decreasing the protein aggregation burden is a possible disease-modifying strategy to tackle MJD and other neurodegenerative disorders for which only symptomatic treatments are currently available. We performed a drug repurposing screening to identify inhibitors of Atx3 aggregation with known toxicological and pharmacokinetic profiles. Interestingly, dopamine hydrochloride and other catecholamines are among the most potent inhibitors of Atx3 aggregation in vitro. Our results indicate that low micromolar concentrations of dopamine markedly delay the formation of mature amyloid fibrils of mutant Atx3 through the inhibition of the earlier oligomerization steps. Although dopamine itself does not cross the blood-brain barrier, dopamine levels in the brain can be increased by low doses of dopamine precursors and dopamine agonists commonly used to treat Parkinsonian symptoms. In agreement, treatment with levodopa ameliorated motor symptoms in a C. elegans model of MJD. These findings suggest a possible application of dopaminergic drugs to halt or reduce Atx3 accumulation in the brains of MJD patients.

The overarching effects of vestibular deficit: Imbalance, anxiety, and spatial disorientation

BackgroundComorbid Balance, Anxiety, and Spatial symptoms are observed in neurodevelopmental disorders and aging. Each of these symptoms was studied separately in association with vestibular hypofunction. We aimed to investigate whether such a diffuse range of symptoms has common vestibular pathophysiology. Specifically, we tested whether this Triad of dysfunctions is associated with central or peripheral vestibular hypofunction. We also assessed the possible contribution of semicircular canals (SCCs) vs. saccular function. MethodsWe tested patients with Peripheral bilateral and unilateral Vestibular Hypofunction (PVH), Machado Joseph Disease (MJD) with cerebellar and central bilateral vestibular hypofunction, and healthy controls. SCCs and sacculi functioning were evaluated by the video Head Impulse Test (vHIT) and cervical Vestibular Evoked Myogenic Potentials (cVEMP), respectively. Balance was assessed by the Activities-specific Balance Confidence scale (ABC), anxiety by the Hamilton Anxiety Rating Scale (HAM-A), and spatial orientation by the Object Perspective Taking test (OPT-t). ResultsPVH patients with vestibular SCCs and saccular hypofunction presented the Triad of symptoms, imbalance, anxiety, and spatial disorientation. MJD patients with SCCs-related vestibular hypofunction but preserved saccular-related vestibular function presented with a partial profile of imbalance and spatial disorientation. ConclusionsThe present study provides evidence that peripheral vestibular hypofunction is associated with the Triad of dysfunctions, i.e., imbalance, anxiety, and spatial disorientation. The combination of SCCs and saccular hypofunction seems to contribute to the emergence of the Triad of symptoms.

Tissue-Specific Vulnerability to Apoptosis in Machado-Joseph Disease.

Machado-Joseph disease (MJD) is a dominant neurodegenerative disease caused by an expanded CAG repeat in the ATXN3 gene encoding the ataxin-3 protein. Several cellular processes, including transcription and apoptosis, are disrupted in MJD. To gain further insights into the extent of dysregulation of mitochondrial apoptosis in MJD and to evaluate if expression alterations of specific apoptosis genes/proteins can be used as transcriptional biomarkers of disease, the expression levels of BCL2, BAX and TP53 and the BCL2/BAX ratio (an indicator of susceptibility to apoptosis) were assessed in blood and post-mortem brain samples from MJD subjects and MJD transgenic mice and controls. While patients show reduced levels of blood BCL2 transcripts, this measurement displays low accuracy to discriminate patients from matched controls. However, increased levels of blood BAX transcripts and decreased BCL2/BAX ratio are associated with earlier onset of disease, indicating a possible association with MJD pathogenesis. Post-mortem MJD brains show increased BCL2/BAX transcript ratio in the dentate cerebellar nucleus (DCN) and increased BCL2/BAX insoluble protein ratio in the DCN and pons, suggesting that in these regions, severely affected by degeneration in MJD, cells show signs of apoptosis resistance. Interestingly, a follow-up study of 18 patients further shows that blood BCL2 and TP53 transcript levels increase over time in MJD patients. Furthermore, while the similar levels of blood BCL2, BAX, and TP53 transcripts observed in preclinical subjects and controls is mimicked by pre-symptomatic MJD mice, the expression profile of these genes in patient brains is partially replicated by symptomatic MJD mice. Globally, our findings indicate that there is tissue-specific vulnerability to apoptosis in MJD subjects and that this tissue-dependent behavior is partially replicated in a MJD mouse model.

Horizontal Vestibulo-Ocular Reflex Deficit as a Biomarker for Clinical Disease Onset, Severity, and Progression of Machado-Joseph Disease.

Because of the crucial importance of finding a useful biomarker for further clinical trials in Machado-Joseph disease (MJD), and based on our previous studies, we aimed to evaluate whether the horizontal vestibulo-ocular reflex (VOR) gain could be a reliable neurophysiological biomarker for the clinical onset, severity, and progression of the disease. Thirty-five MJD patients, 11 pre-symptomatic genetically confirmed MJD subjects, and 20 healthy controls underwent a detailed epidemiological and clinical neurological examination including the Scale for the Assessment and Rating of Ataxia (SARA). Their VOR gain was measured using the video Head Impulse Test system. Twenty of the MJD patients were re-tested after a period of 1-3 years. Horizontal VOR gain was abnormal in 92% of MJD, 54% pre-symptomatic, and 0% healthy controls. Horizontal VOR gain in the MJD group was significantly negatively correlated with SARA score in the first (r=0.66, p<0.001) and second (r=0.61, p<0.001) examinations. There was also a significant negative correlation between the percentage of change in horizontal VOR gain and the percentage of change in SARA score across both examinations (r=-0.54, p < 0.05). A regression model of the SARA score with the horizontal VOR gain and disease duration as predictors demonstrated that both the horizontal VOR gain and the disease duration had an independent contribution to the prediction of the SARA score. The horizontal VOR gain seems to be a reliable biomarker for the clinical onset, severity, and progression of MJD and could be used in further clinical studies.

"I Do Not Know How You Feel and How I Feel About That": Mentalizing Impairments in Machado-Joseph Disease.

Machado Joseph disease (MJD), also known as spinocerebellar ataxia type 3 (SCA3), is an autosomal dominant neurodegenerative disease. Mentalizing is the ability to think and understand the mental state of the other and of the self in terms of thoughts, feelings, and intentions. The aim of this study is to fill the gap in our understanding of mentalizing in MJD since there is currently very little and inconsistent research on MJD and mentalizing. A total of 18 Jews of Yemenite origin with clinically and genetically confirmed MJD, 5 pre-symptomatic MJD with a positive genetic test, and 17 Jews of Yemenite origin healthy controls, underwent a battery of tests consisting of reading the mind in the eyes (RME), Toronto Alexithymia Scale (TAS-20), and false belief test (FBt). The MJD group scored lower on the RME and FBt, and higher on TAS-20 test compared to control. A significant negative correlation was found between disease duration and RME score. All the pre-symptomatic participants scored within the normal clinical range in all tests. MJD patients demonstrated a widespread deficiency in the ability to mentalizing on a clinical level with autistic characteristics. These impairments may impact the patient's interpsychic experience and daily life interactions and have important clinical implication. Pre-symptomatic participants demonstrated normal mentalizing in all tests, suggesting that the mentalizing impairments do not precede the symptoms of ataxia and are part of the clinical picture of MJD.

How vestibular dysfunction transforms into symptoms of depersonalization and derealization?

BackgroundPsychiatric Depersonalization/Derealization (DPDR) symptoms were demonstrated in patients with peripheral vestibular disorders. However, only semicircular canals (SCCs) dysfunction was evaluated, therefore, otoliths' contribution to DPDR is unknown. Also, DPDR symptoms in patients with central vestibular dysfunction are presently unknown. DPDR was also studied in the context of spatial disorientation and anxiety, but the relation of these cognitive and emotional functions to vestibular dysfunction requires clarification. MethodsWe tested patients with peripheral Bilateral Vestibular Hypofunction (pBVH), Machado Joseph Disease (MJD) with cerebellar and central bilateral vestibular hypofunction, and healthy controls. Participants completed the video Head Impulse Test (vHIT) for SCCs function, cervical Vestibular Evoked Myogenic Potentials test (cVEMPt) for sacculi function, Body Sensation Questionnaire (BSQ) for panic anxiety, Object Perspective-Taking test (OPTt) for spatial orientation and Cox & Swinson DPDR inventory for DPDR symptoms. ResultspBVH patients showed significant SCCs and sacculi dysfunction, spatial disorientation, elevated panic anxiety, and DPDR symptoms. MJD patients showed significant SCCs hypofunction but preserved sacculi function, spatial disorientation but normal levels of panic anxiety and DPDR symptoms. Only pBVH patients demonstrated a positive correlation between the severity of the DPDR and spatial disorientation and panic anxiety. ConclusionsDPDR develops in association with sacculi dysfunction, either with or without SSCs dysfunction. Spatial disorientation and anxiety seem to mediate the transformation of vestibular dysfunction into DPDR symptoms. DPDR does not develop in MJD with central vestibular hypofunction but a normal saccular response. We propose a three-step model that describes the development of DPDR symptoms in vestibular patients.

Short Communication: Restrictions in care following the COVID-19 pandemic severely impacted Machado-Joseph disease patients: a study in the Azores Islands, Portugal.

This qualitative study describes how the restrictions imposed by the COVID-19 pandemic impacted on Machado-Joseph disease (MJD) patients and their care, in the island of São Miguel (the Azores, Portugal). In-person semi-structured interviews were conducted with 11 participants, including patients, family members, healthcare professionals, and care providers. Main findings highlighted the key role played by the local association in psychosocial and healthcare for MJD patients and families, and the adverse effects on their care following the onset of the COVID-19 pandemic. In particular, hindered access to the day-care centre increased isolation and had a negative impact on mental health and disease progression. For persons with a progressive and severe neurological disease, there is no “back to normal.” Future restrictive measures ensuing need to be accompanied by a careful definition of daily care routines for patients.

KPNB1 modulates the Machado–Joseph disease protein ataxin-3 through activation of the mitochondrial protease CLPP

Machado–Joseph disease (MJD) is characterized by a pathological expansion of the polyglutamine (polyQ) tract within the ataxin-3 protein. Despite its primarily cytoplasmic localization, polyQ-expanded ataxin-3 accumulates in the nucleus and forms intranuclear aggregates in the affected neurons. Due to these histopathological hallmarks, the nucleocytoplasmic transport machinery has garnered attention as an important disease relevant mechanism. Here, we report on MJD cell model-based analysis of the nuclear transport receptor karyopherin subunit beta-1 (KPNB1) and its implications in the molecular pathogenesis of MJD. Although directly interacting with both wild-type and polyQ-expanded ataxin-3, modulating KPNB1 did not alter the intracellular localization of ataxin-3. Instead, overexpression of KPNB1 reduced ataxin-3 protein levels and the aggregate load, thereby improving cell viability. On the other hand, its knockdown and inhibition resulted in the accumulation of soluble and insoluble ataxin-3. Interestingly, the reduction of ataxin-3 was apparently based on protein fragmentation independent of the classical MJD-associated proteolytic pathways. Label-free quantitative proteomics and knockdown experiments identified mitochondrial protease CLPP as a potential mediator of the ataxin-3-degrading effect induced by KPNB1. We confirmed reduction of KPNB1 protein levels in MJD by analyzing two MJD transgenic mouse models and induced pluripotent stem cells (iPSCs) derived from MJD patients. Our results reveal a yet undescribed regulatory function of KPNB1 in controlling the turnover of ataxin-3, thereby highlighting a new potential target of therapeutic value for MJD.

Altered glucose metabolism and its association with carbonic anhydrase 8 in Machado-Joseph Disease.

Machado-Joseph disease (MJD), also known as spinocerebellar ataxia type 3 (SCA3), is an autosomal dominant neurodegenerative disease. This disorder is caused by polyglutamine (polyQ)-containing mutant ataxin-3, which tends to misfold and aggregate in neuron cells. We previously demonstrated a protective function of carbonic anhydrase 8 (CA8) in MJD disease models and a decreased glycolytic activity associated with down-regulated CA8 in a human osteosarcoma (OS) cell model. Given that a reduction in body weight accompanied by gait and balance instability was observed in MJD patients and transgenic (Tg) mice, in this study, we aimed to examine whether metabolic defects are associated with MJD and whether CA8 expression is involved in metabolic dysfunction in MJD. Our data first showed that glucose uptake ability decreases in cells harboring mutant ataxin-3, but increases in cells overexpressing CA8. In addition, the expressions of glucose transporter 3 (GLUT3) and phosphofructokinase-1 (PFK1) were significantly decreased in the presence of mutant ataxin-3. Consistently, immunohistochemistry (IHC) showed that GLUT3 was less expressed in cerebella of aged MJD Tg mice, indicating that the dysfunction of GLUT3 may be associated with late-stage disease. On the other hand, transient down-regulation of CA8 revealed decreased expressions of GLUT3 and PFK1 in HEK293 cells harboring wild-type (WT) ataxin-3, but no further reduction of GLUT3 and PFK1 expressions were observed in HEK293 cells harboring mutant ataxin-3. Moreover, immunoprecipitation (IP) and immunofluorescence (IF) demonstrated that interactions exist between ataxin-3, CA8 and GLUT3 in MJD cellular and Tg models. These lines of evidence suggest that CA8 plays an important role in glucose metabolism and has different impacts on cells with or without mutant ataxin-3. Interestingly, the decreased relative abundance of Firmicutes/Bacteroidetes (F/B) ratio in the feces of aged MJD Tg mice coincided with weight loss and metabolic dysfunction in MJD. Taken together, our results are the first to demonstrate the effects of CA8 on glucose metabolism and its involvement in the metabolic defects in MJD disease. Further investigations will be required to clarify the underlying mechanisms for the metabolic defects associated with MJD.

Cerebellar morphometric and spectroscopic biomarkers for Machado-Joseph Disease

Machado-Joseph disease (MJD) or Spinocerebellar ataxia type 3 (SCA3) is the most common form of dominant SCA worldwide. Magnetic Resonance Imaging (MRI) and Proton Magnetic Resonance Spectroscopy (1H-MRS) provide promising non-invasive diagnostic and follow-up tools, also serving to evaluate therapies efficacy. However, pre-clinical studies showing relationship between MRI-MRS based biomarkers and functional performance are missing, which hampers an efficient clinical translation of therapeutics. This study assessed motor behaviour, neurochemical profiles, and morphometry of the cerebellum of MJD transgenic mice and patients aiming at establishing magnetic-resonance-based biomarkers. 1H-MRS and structural MRI measurements of MJD transgenic mice were performed with a 9.4 Tesla scanner, correlated with motor performance on rotarod and compared with data collected from human patients. We found decreased cerebellar white and grey matter and enlargement of the fourth ventricle in both MJD mice and human patients as compared to controls. N-acetylaspartate (NAA), NAA + N-acetylaspartylglutamate (NAA + NAAG), Glutamate, and Taurine, were significantly decreased in MJD mouse cerebellum regardless of age, whereas myo-Inositol (Ins) was increased at early time-points. Lower neurochemical ratios levels (NAA/Ins and NAA/total Choline), previously correlated with worse clinical status in SCAs, were also observed in MJD mice cerebella. NAA, NAA + NAAG, Glutamate, and Taurine were also positively correlated with MJD mice motor performance. Importantly, these 1H-MRS results were largely analogous to those found for MJD in human studies and in our pilot data in human patients. We have established a magnetic resonance-based biomarker approach to monitor novel therapies in preclinical studies and human clinical trials.

A Variant in Genes of the NPY System as Modifier Factor of Machado-Joseph Disease in the Chinese Population.

Recently, NPY overexpression has been proposed to alleviate motor deficits and neuropathy in Machado-Joseph disease (MJD) mouse models, indicating its neuroprotective role in the pathogenesis of MJD. We aimed to evaluate the association between SNPs in NPY and its receptors and the susceptibility of MJD in the Chinese population. Moreover, we investigated whether these SNPs modulate the age at onset (AO) of MJD. In total, 527 MJD patients and 487 healthy controls were enrolled in the study, and four specific selected SNPs (rs16139, rs3037354, rs2234759, and rs11100494) in NPY and its receptor genes were genotyped. In this study, the genotypic frequency using the dominant model and the allelic distribution of rs11100494 in NPY5R revealed a significant difference between the MJD and control group during the first-stage analysis (P = 0.048 and P = 0.024, respectively). After we expanded the sample size, significant differences were observed between the two groups using the dominant model in genotypic and allelic distribution (P = 0.034, P = 0.046, and P = 0.016, respectively). No significant differences in genotypic and allelic distribution were found between the MJD and control groups for the other three SNPs. All selected SNPs had no significant effect on the AO of MJD. The association of rs11100494 in the NPY5R gene and susceptibility of MJD suggested that the NPY system might be implicated in the pathogenesis of MJD. Our study demonstrated the existence of other genetic modifiers in MJD, along with CAG expansion and known genetic modifier factors, which might lead to a better understanding of MJD pathogenesis.

Genetic Variation in ATXN3 (Ataxin-3) 3'UTR: Insights into the Downstream Regulatory Elements of the Causative Gene of Machado-Joseph Disease/Spinocerebellar Ataxia Type 3.

Untranslated regions are involved in the regulation of transcriptional and post-transcriptional processes. Characterization of these regions remains poorly explored for ATXN3, the causative gene of Machado-Joseph disease (MJD). Although a few genetic modifiers have been identified for MJD age at onset (AO), they only explain a small fraction of the AO variance. Our aim was to analyse variation at the 3'UTR of ATXN3 in MJD patients, analyse its impact on AO and attempt to build haplotypes that might discriminate between normal and expanded alleles.After assessing ATXN3 3'UTR variants in molecularly confirmed MJD patients, an in silico analysis was conducted to predict their functional impact (e.g. their effect on miRNA-binding sites). Alleles in cis with the expanded (CAG)n were inferred from family data, and haplotypes were built. The effect of the alternative alleles on the AO and on SARA and NESSCA ataxia scales was tested.Nine variants, all previously described, were found. For eight variants, in silico analyses predicted (a) deleterious effects (rs10151135; rs55966267); (b) changes on miRNA-binding sites (rs11628764; rs55966267; rs709930) and (c) alterations of RNA-binding protein (RBP)-binding sites (rs1055996; rs910369; rs709930; rs10151135; rs3092822; rs7158733). Patients harbouring the alternative allele at rs10151135 had significantly higher SARA Axial subscores (p = 0.023), comparatively with those homozygous for the reference allele. Ten different haplotypes were obtained, one of which was exclusively found in cis with the expanded and four with the normal allele. These findings, which are relevant for the design of allele-specific therapies, warrant further investigation in independent MJD cohorts.

Pathophysiological interplay between O-GlcNAc transferase and the Machado–Joseph disease protein ataxin-3

Aberrant O-GlcNAcylation, a protein posttranslational modification defined by the O-linked attachment of the monosaccharide N-acetylglucosamine (O-GlcNAc), has been implicated in neurodegenerative diseases. However, although many neuronal proteins are substrates for O-GlcNAcylation, this process has not been extensively investigated in polyglutamine disorders. We aimed to evaluate the enzyme O-GlcNAc transferase (OGT), which attaches O-GlcNAc to target proteins, in Machado-Joseph disease (MJD). MJD is a neurodegenerative condition characterized by ataxia and caused by the expansion of a polyglutamine stretch within the deubiquitinase ataxin-3, which then present increased propensity to aggregate. By analyzing MJD cell and animal models, we provide evidence that OGT is dysregulated in MJD, therefore compromising the O-GlcNAc cycle. Moreover, we demonstrate that wild-type ataxin-3 modulates OGT protein levels in a proteasome-dependent manner, and we present OGT as a substrate for ataxin-3. Targeting OGT levels and activity reduced ataxin-3 aggregates, improved protein clearance and cell viability, and alleviated motor impairment reminiscent of ataxia of MJD patients in zebrafish model of the disease. Taken together, our results point to a direct interaction between OGT and ataxin-3 in health and disease and propose the O-GlcNAc cycle as a promising target for the development of therapeutics in the yet incurable MJD.

Angular vestibulo ocular reflex loss with preserved saccular function in Machado-Joseph disease

ObjectiveTo provide a comprehensive evaluation of the vestibular function in Machado-Joseph Disease (MJD). Methods21 MJD patients and 19 healthy Controls underwent a detailed clinical neuro-otological evaluation including VOR gain of all six semicircular canals by video Head Impulse Test (vHIT), remaining horizontal VOR function by Suppression Head Impulse test (SHIMP), and saccular function by cervical Vestibular Evoked Myogenic Potentials (cVEMP). ResultsAll MJD had significantly lower VOR gain in all six semicircular canals (p < 0.001) with a mean ± SEM of horizontal gain of 0.52 ± 0.04 and vertical gain of 0.57 ± 0.03 versus Controls' gain of 0.95 ± 0.01 and 0.81 ± 0.02, respectively (p < 0.001). MJD showed also a significantly lower VOR gain on the SHIMP test with left gain of 0.51 ± 0.04 and right gain of 0.46 ± 0.03 versus Controls' gain of 0.79 ± 0.01 and 0.83 ± 0.03, respectively (p < 0.001). In contrast, MJD had normal saccular function reflected by the presence of cVEMP response in 18/20 patients and in 12/17 of Controls, with a non-significant difference between MJD and Controls of P13 and N23 peaks latency and normalized peak-to-peak amplitude. ROC analysis of horizontal VOR gain resulted in an area under the curve of 0.993 making the average lateral canals' VOR gain an excellent classifier of MJD vs Controls. ConclusionsHorizontal and vertical VOR impairment with preserved sacculo-collic function seems to be a distinctive feature of MJD and could be explained by selective, mostly medial and superior vestibular nuclei degeneration. This study further supports the idea that horizontal VOR gain measured by vHIT could be a potential neurophysiological biomarker of MJD.

Overexpression of FKH-2/FOXG1 is neuroprotective in a C. elegans model of Machado-Joseph disease

Machado-Joseph disease (MJD), also known as spinocerebellar ataxia type 3 (SCA3), is the most common form of dominantly inherited ataxia worldwide. This disease is caused by an expanded CAG repeat in the coding region of ATXN3. Due to our incomplete understanding of mechanisms and molecular pathways related to this disease, there are no therapies that successfully treat core MJD patients. Therefore, the identification of new candidate targets related to this disease is needed.In this study, we performed a large-scale RNA interference (RNAi) screen of 387 transcription factor genes leading to the identification of several modifiers (suppressors and enhancers) of impaired motility phenotypes in a mutant ATXN3 transgenic C. elegans model. We showed that inactivation of one particular gene, fkh-2/FOXG1, enhanced the motility defect, neurodegeneration and reduced longevity in our MJD models. Opposite to genetic inactivation, the overexpression of fkh-2 rescued the impaired motility, shortened-lifespan, and neurodegeneration phenotypes of mutant ATXN3 transgenics. We found that overexpression of FKH-2/FOXG1 in ATXN3 mutant worms is neuroprotective.Using our transgenic ATXN3 C. elegans models and the screening of an RNAi library, we gained insights into the pathways contributing to neurodegeneration, and found that FKH-2/FOXG1 has neuroprotective activity. These findings may aid the development of novel therapeutic interventions for MJD.

Trehalose in Machado-Joseph Disease: Safety, Tolerability, and Efficacy.

Machado-Joseph disease (MJD) is relatively prevalent among the Yemenite Jewish subpopulation living in Israel. Currently, there is no treatment able to modify the disease progression. Trehalose is a disaccharide with protein-stabilizing and autophagy-enhancing properties. In animal models of MJD, trehalose showed reduction of cerebellar lesion size and improved motor function. This study was designed to be a proof-of-concept, phase 2 study lasting 6 to 12 months, to determine the safety, tolerability, and efficacy of weekly IV administration of 15 g or 30 g 10% trehalose solution in 14 MJD patients. Primary endpoints were safety and tolerability, which were assessed by various clinical and laboratory tests. Secondary endpoints were changes in the Scale for Assessment and Rating of Ataxia (SARA) score, Neurological Examination Score for Spinocerebellar Ataxia (NESSCA), time to do 9-hole peg test (9HPT), time to do 8-meter walk (8MW), and quality of life assessed by the World Health Organization Quality-of-Life Questionnaire-BREF (WHOQoL-BREF). Trehalose was well tolerated, and no serious drug-related adverse events were noted. The average SARA score, NESSCA, and time to do 9HPT and 8MW and the WHOQoL-BREF for all patients remained stable at 6 months. Six patients received treatment for as long as 12 months and continued to remain stable on all the above tests. IV trehalose seems to be safe in humans and probably effective to stabilize neurological impairment in MJD.

Ibuprofen enhances synaptic function and neural progenitors proliferation markers and improves neuropathology and motor coordination in Machado-Joseph disease models.

Machado-Joseph disease or spinocerebellar ataxia type 3 is an inherited neurodegenerative disease associated with an abnormal glutamine over-repetition within the ataxin-3 protein. This mutant ataxin-3 protein affects several cellular pathways, leading to neuroinflammation and neuronal death in specific brain regions resulting in severe clinical manifestations. Presently, there is no therapy able to modify the disease progression. Nevertheless, anti-inflammatory pharmacological intervention has been associated with positive outcomes in other neurodegenerative diseases. Thus, the present work aimed at investigating whether ibuprofen treatment would alleviate Machado-Joseph disease. We found that ibuprofen-treated mouse models presented a significant reduction in the neuroinflammation markers, namely Il1b and TNFa mRNA and IKB-α protein phosphorylation levels. Moreover, these mice exhibited neuronal preservation, cerebellar atrophy reduction, smaller mutant ataxin-3 inclusions and motor performance improvement. Additionally, neural cultures of Machado-Joseph disease patients' induced pluripotent stem cells-derived neural stem cells incubated with ibuprofen showed increased levels of neural progenitors proliferation and synaptic markers such as MSI1, NOTCH1 and SYP. These findings were further confirmed in ibuprofen-treated mice that display increased neural progenitor numbers (Ki67 positive) in the subventricular zone. Furthermore, interestingly, ibuprofen treatment enhanced neurite total length and synaptic function of human neurons. Therefore, our results indicate that ibuprofen reduces neuroinflammation and induces neuroprotection, alleviating Machado-Joseph disease-associated neuropathology and motor impairments. Thus, our findings demonstrate that ibuprofen treatment has the potential to be used as a neuroprotective therapeutic approach in Machado-Joseph disease.

Assessment of Bone Mineral Density of Patients with Spinocerebellar Ataxia Type 3.

ObjectiveMachado-Joseph disease (MJD) is a spinocerebellar ataxia, and osteoporosis is a multifactor disease that may affect patients with neurologic conditions. The frequency of osteoporosis among MJD patients, however, has not been studied. The purpose of this study is to evaluate bone mineral density (BMD) and identify correlations between clinical factors and frequency of vertebral fractures in patients with MJD.MethodsClinical data, lumbar X-rays and BMD data were obtained in 30 patients with MJD.ResultsTen patients (33.3%) showed low BMD in at least one of the sites studied based on Z-scores. The Z-score correlated directly with body mass index, and the femoral neck Z-score was inversely correlated with cytosine-adenine-guanine (CAG) expansion. There was no correlation between BMD and other clinical factors. Forty-three percent of the patients reported previous pathologic fractures. Five patients (16.7%) had at least one fracture detected by lumbar X-ray.ConclusionLow BMD and fractures are frequent among MJD patients, and careful management of BMD may be beneficial for these patients.